Trial Outcomes & Findings for Sym004 in Subjects With Stage IV Non-small Cell Lung Cancer (NCT NCT02083679)

NCT ID: NCT02083679

Last Updated: 2016-10-25

Results Overview

DLT: any National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 Grade 4 hematologic or Grade 3/4 non-hematologic toxicities that occurred during DLT observation period and were considered by Investigator to be at least possibly related to trial treatment, and were confirmed by Safety Monitoring Committee (SMC), with exception of Grade 4 neutropenia for not \>5 days; Grade 4 lymphocytopenia/ thrombocytopenia for not \>5 days; fatigue/headache lasting \< 7 days; nausea/vomiting/diarrhoea lasting not \>3 days; asymptomatic Grade 3 increase in liver function tests that resolve to baseline within 7 days; Mucositis \>= Grade 3 lasting \< 7 days; Grade 3 hyperglycemia that resolves in \< 7 days; any laboratory values \>Grade 3 without any clinical correlate (resolve within 5 days); Grade 3 skin toxicities that resolve to Grade 2 within 7 days; Grade 3/4 hypomagnesemia that resolves within 5 days. Subjects with DLTs presented based on investigator and SMC decision.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

15 participants

Primary outcome timeframe

Day 1 to Day 21 of Cycle 1

Results posted on

2016-10-25

Participant Flow

The trial was conducted at 5 clinical trial sites within France and the United States. First subject first visit: 03 July 2014 and last subject last visit: 31 August 2015. Clinical data cut-off date: 16 September 2015

This study was planned to be conducted in 2 parts; Part 1 was the dose escalation part and Part 2 was the expansion cohort. However, due to premature termination of the trial by the Sponsor, the Expansion Cohort (Part 2) was not conducted.

Participant milestones

Participant milestones
Measure	Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine Sym004 administered as an intravenous infusion at a dose of 6 milligram per kilogram (mg/kg) weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the investigational medicinal product (IMP) in combination with platinum-doublet chemotherapy regimen of cisplatin/gemcitabine (cisplatin 75 milligram per meter square (mg/m\^2) on Day 1 plus gemcitabine 1250 mg/m\^2 on Days 1 and 8 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of cisplatin/pemetrexed (cisplatin 75 mg/m\^2 plus pemetrexed 500 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin area under the concentration-time curve (AUC) = 6 milligram per millilitre per minute \[mg/mL/min\] plus paclitaxel 225 mg/m\^2 on Day 1 of 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel Sym004 administered as an intravenous infusion at a dose 6 mg/kg on Day 1 and 12 mg/kg on Day 8 of a 3-Week cycle until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin AUC = 6 mg/mL/min plus paclitaxel 225 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).
Overall Study STARTED	3	6	3	3
Overall Study COMPLETED	3	6	3	3
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Sym004 in Subjects With Stage IV Non-small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine n=3 Participants Sym004 administered as an intravenous infusion at a dose of 6 milligram per kilogram (mg/kg) weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the investigational medicinal product (IMP) in combination with platinum-doublet chemotherapy regimen of cisplatin/gemcitabine (cisplatin 75 milligram per meter square (mg/m\^2) on Day 1 plus gemcitabine 1250 mg/m\^2 on Days 1 and 8 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed n=6 Participants Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of cisplatin/pemetrexed (cisplatin 75 mg/m\^2 plus pemetrexed 500 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel n=3 Participants Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin area under the concentration-time curve (AUC) = 6 milligram per millilitre per minute \[mg/mL/min\] plus paclitaxel 225 mg/m\^2 on Day 1 of 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel n=3 Participants Sym004 administered as an intravenous infusion at a dose 6 mg/kg on Day 1 and 12 mg/kg on Day 8 of a 3-Week cycle until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin AUC = 6 mg/mL/min plus paclitaxel 225 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Total n=15 Participants Total of all reporting groups
Age, Continuous	61.8 years STANDARD_DEVIATION 7.05 • n=99 Participants	59.1 years STANDARD_DEVIATION 6.44 • n=107 Participants	58.9 years STANDARD_DEVIATION 11.09 • n=206 Participants	44.8 years STANDARD_DEVIATION 10.86 • n=7 Participants	56.7 years STANDARD_DEVIATION 9.78 • n=31 Participants
Sex: Female, Male Female	0 Participants n=99 Participants	2 Participants n=107 Participants	1 Participants n=206 Participants	0 Participants n=7 Participants	3 Participants n=31 Participants
Sex: Female, Male Male	3 Participants n=99 Participants	4 Participants n=107 Participants	2 Participants n=206 Participants	3 Participants n=7 Participants	12 Participants n=31 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 21 of Cycle 1

Population: The dose limiting toxicity set included all 15 subjects in the safety analysis set (SAF) who received all planned trial medication doses during the first 21 days following the first dose of Sym004.

Outcome measures

Outcome measures
Measure	Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine n=3 Participants Sym004 administered as an intravenous infusion at a dose of 6 milligram per kilogram (mg/kg) weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the investigational medicinal product (IMP) in combination with platinum-doublet chemotherapy regimen of cisplatin/gemcitabine (cisplatin 75 milligram per meter square (mg/m\^2) on Day 1 plus gemcitabine 1250 mg/m\^2 on Days 1 and 8 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed n=6 Participants Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of cisplatin/pemetrexed (cisplatin 75 mg/m\^2 plus pemetrexed 500 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel n=3 Participants Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin area under the concentration-time curve (AUC) = 6 milligram per millilitre per minute \[mg/mL/min\] plus paclitaxel 225 mg/m\^2 on Day 1 of 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel n=3 Participants Sym004 administered as an intravenous infusion at a dose 6 mg/kg on Day 1 and 12 mg/kg on Day 8 of a 3-Week cycle until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin AUC = 6 mg/mL/min plus paclitaxel 225 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).
Number of Subjects With Dose Limiting Toxicities (DLTs) Investigator	2 Subjects	1 Subjects	1 Subjects	0 Subjects
Number of Subjects With Dose Limiting Toxicities (DLTs) SMC	2 Subjects	1 Subjects	0 Subjects	0 Subjects

SECONDARY outcome

Timeframe: Day 1 up to 28 days after last dose of study drug (up to 53 weeks)

Population: The safety analysis set included all 15 subjects who were administered any dose of the trial medication.

An adverse event (AE) was defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. AEs were considered treatment emergent if they started on or after the day of first administration of the first trial treatment given (Sym004 or one of the individual Platinum-Doublet therapies) or if they worsened after receiving first dose of treatment.

Outcome measures

Outcome measures
Measure	Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine n=3 Participants Sym004 administered as an intravenous infusion at a dose of 6 milligram per kilogram (mg/kg) weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the investigational medicinal product (IMP) in combination with platinum-doublet chemotherapy regimen of cisplatin/gemcitabine (cisplatin 75 milligram per meter square (mg/m\^2) on Day 1 plus gemcitabine 1250 mg/m\^2 on Days 1 and 8 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed n=6 Participants Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of cisplatin/pemetrexed (cisplatin 75 mg/m\^2 plus pemetrexed 500 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel n=3 Participants Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin area under the concentration-time curve (AUC) = 6 milligram per millilitre per minute \[mg/mL/min\] plus paclitaxel 225 mg/m\^2 on Day 1 of 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel n=3 Participants Sym004 administered as an intravenous infusion at a dose 6 mg/kg on Day 1 and 12 mg/kg on Day 8 of a 3-Week cycle until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin AUC = 6 mg/mL/min plus paclitaxel 225 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).
Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death TEAEs	3 subjects	6 subjects	3 subjects	3 subjects
Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death Serious TEAEs	3 subjects	5 subjects	3 subjects	3 subjects
Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death TEAE leading to Discontinuation	1 subjects	3 subjects	0 subjects	2 subjects
Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death TEAEs Leading to Death	0 subjects	0 subjects	0 subjects	0 subjects

Adverse Events

Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine

Serious events: 3 serious events

Other events: 3 other events

Deaths: 0 deaths

Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed

Serious events: 5 serious events

Other events: 6 other events

Deaths: 0 deaths

Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel

Serious events: 3 serious events

Other events: 3 other events

Deaths: 0 deaths

Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel

Serious events: 3 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Merck KGaA Communication Center

Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine n=3 participants at risk Sym004 administered as an intravenous infusion at a dose of 6 milligram per kilogram (mg/kg) weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the investigational medicinal product (IMP) in combination with platinum-doublet chemotherapy regimen of cisplatin/gemcitabine (cisplatin 75 milligram per meter square (mg/m\^2) on Day 1 plus gemcitabine 1250 mg/m\^2 on Days 1 and 8 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed n=6 participants at risk Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of cisplatin/pemetrexed (cisplatin 75 mg/m\^2 plus pemetrexed 500 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel n=3 participants at risk Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin area under the concentration-time curve (AUC) = 6 milligram per millilitre per minute \[mg/mL/min\] plus paclitaxel 225 mg/m\^2 on Day 1 of 3-Week cycle intravenously for a maximum of 6 treatment cycles).	Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel n=3 participants at risk Sym004 administered as an intravenous infusion at a dose 6 mg/kg on Day 1 and 12 mg/kg on Day 8 of a 3-Week cycle until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin AUC = 6 mg/mL/min plus paclitaxel 225 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).
Blood and lymphatic system disorders Thrombocytopenia	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Cardiac disorders Atrial fibrillation	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Ear and labyrinth disorders Hearing impaired	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Gastrointestinal disorders Abdominal pain upper	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Gastrointestinal disorders Nausea	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Gastrointestinal disorders Stomatitis	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Gastrointestinal disorders Vomiting	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
General disorders Non-cardiac chest pain	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Infections and infestations Bacterial sepsis	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Infections and infestations Device related infection	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Infections and infestations Device related sepsis	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Infections and infestations Staphylococcal sepsis	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Injury, poisoning and procedural complications Infusion related reaction	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Investigations Neutrophil count decreased	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Investigations Platelet count decreased	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Investigations White blood cell count decreased	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Metabolism and nutrition disorders Diabetes mellitus	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Metabolism and nutrition disorders Hypomagnesaemia	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell carcinoma	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Nervous system disorders Syncope	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Nervous system disorders Tremor	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Renal and urinary disorders Acute kidney injury	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Renal and urinary disorders Urinary bladder polyp	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Respiratory, thoracic and mediastinal disorders Pneumothorax	66.7% 2/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Vascular disorders Deep vein thrombosis	33.3% 1/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Vascular disorders Peripheral vascular disorder	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	16.7% 1/6 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)	0.00% 0/3 • Day 1 up to 28 days after last dose of study drug (up to 53 weeks)